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Over 140 proteins localized to primary cilia, which are sensory organelles essential for vertebrate development, are implicated.\n                    <jats:italic>TMEM17<\/jats:italic>\n                    encodes a transmembrane protein at the ciliary transition zone and was previously proposed as a potential ciliopathy gene, based on reports of individuals from two families with orofaciodigital syndrome type 6 (OFD6) and Joubert syndrome (JS). Here, we report two unrelated fetuses with occipital encephalocele, polydactyly, and kidney cysts, in whom exome sequencing identified a founder homozygous missense variant (Arg94Trp) in TMEM17, affecting a highly conserved residue. This expands the\n                    <jats:italic>TMEM17<\/jats:italic>\n                    \u2010associated phenotypic spectrum to include Meckel syndrome (MKS). Comprehensive functional analyses of all known\n                    <jats:italic>TMEM17<\/jats:italic>\n                    variants, using patient tissues\/cells and a\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>C. elegans<\/jats:italic>\n                    <\/jats:styled-content>\n                    model system, demonstrate a loss\u2010of\u2010function mechanism. Our study reveals severe functional consequences, including TMEM17 destabilization and mislocalization, anomalies in cilium composition and function, and abrogation of Sonic Hedgehog signaling. These experiments confirm the pathogenicity of all\n                    <jats:italic>TMEM17<\/jats:italic>\n                    variants and underscore its essential role at the ciliary transition zone. Collectively, our findings establish\n                    <jats:italic>TMEM17<\/jats:italic>\n                    as a\n                    <jats:italic>bona fide<\/jats:italic>\n                    ciliopathy gene, associated with a wide phenotypic spectrum ranging from viable syndromes (OFD6 and JS) to a fetal\u2010lethal condition (MKS).\n                  <\/jats:p>","DOI":"10.1111\/cge.70042","type":"journal-article","created":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T03:39:54Z","timestamp":1755833994000},"page":"305-315","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Missense Variants in the Second Transmembrane Domain of\n                    <scp>TMEM17<\/scp>\n                    Disrupt Its Stability and Function and Lead to a Wide Phenotypic Spectrum of Ciliopathies"],"prefix":"10.1111","volume":"109","author":[{"given":"Lucile","family":"Boutaud","sequence":"first","affiliation":[{"name":"INSERM UMR 1163, Institut Imagine Universit\u00e9 Paris Cit\u00e9  Paris France"},{"name":"Service de M\u00e9decine G\u00e9nomique des Maladies Rares H\u00f4pital Universitaire Necker\u2010Enfants Malades  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunmei","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Biochemistry Simon Fraser University  Burnaby British Columbia Canada"},{"name":"Centre for Cell Biology, Development, and Disease Simon Fraser University  Burnaby British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Candice","family":"Moncler","sequence":"additional","affiliation":[{"name":"INSERM UMR 1163, Institut Imagine Universit\u00e9 Paris Cit\u00e9  Paris 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